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370 1. Abstract 2. Introduction: Natural Killer Cells Kill [Frontiers in Bioscience, Landmark, 22, 370-384, January 1, 2017] Novel strategies to target cancer stem cells by NK cells; studies in humanized mice Anna K. Kozlowska1,3, Kawaljit Kaur1, Paytsar Topchyan1, Anahid Jewett1,2 1Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA, 2The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA, 3Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland TABLE OF CONTENTS 1. Abstract 2. Introduction: Natural killer cells kill and differentiate cancer stem-like cells 3. Studies of NK cells in xenogeneic implantation of human cells into immunodeficient mouse strains 4. Use of immunodeficient mouse strains in the studies of cancer immunity 5. Humanized mice as preclinical models to study the complexity of human immune system interactions 6. Potential limitations of allogeneic tumor transplantation in humanized mice 7. Are NK cells in humanized mice of sufficient quantity and quality? 8. NK cell receptor downregulation as potential mechanism for the detection of low NK cell frequencies in vivo 9. Adoptive therapy with osteoclast-expanded NK cells eliminates cancer stem-like cells in humanized mice 10. Future of NK cell mediated immunotherapy 11. Acknowledgements 12. References 1. ABSTRACT We have previously shown, that following represent the first line of defense against virally infected selection, natural killer (NK) cells differentiate cancer stem- cells and transformed cells. However, decreased NK like cells (CSCs)/poorly differentiated tumors via secreted cell cytotoxicity in the tumor microenvironment and and membrane bound IFN-gamma and TNF-alpha, peripheral blood of cancer patients, as well as down- leading to prevention of tumor growth and remodeling modulation of CD16 receptors on the surface of NK cells, of the tumor microenvironment. Since conventional have been reported and thought to contribute to cancer therapeutic strategies, including chemotherapy and progression (1, 2). Increasing evidence indicates that the radiotherapy remain unsuccessful in treating stem-like majority of human cancer originates and is maintained tumors, there has been increasing interest in NK cell- by proliferating stem-like populations, known as cancer targeted immunotherapy for the treatment of aggressive stem-like cells (CSCs), which are capable of self- malignacies. In our recent studies, we used a humanized renewal. Even though CSCs are highly susceptible to (hu-BLT) mouse model with transplanted human bone NK cells, they maintain resistance to chemotherapeutic marrow, liver and thymus to demonstrate the efficacy of drugs and radiation through increased expression of adoptive transfer of ex vivo expanded, super-charged NK DNA mismatch repair genes and augmented multi-drug cells in selection and differentiation of stem-like tumors resistance genes (3, 4). within the context of a fully reconstituted human immune system. We have also shown that CSCs differentiated with We have previously shown that NK cells split anergized NK cells prior to implantation in humanized cytotoxicity is suppressed after interaction with healthy mice did not grow or metastasize. In this review, we hematopoietic stem cells and malignant stem-like present current advances in NK cell detection, expansion cells (5-11). It has also been demonstrated that NK cells and therapeutic delivery methods, and discuss the utility lose the ability to mediate cytotoxicity and down-modulate of different humanized mouse models in studying NK cell- CD16 receptor expression upon interaction with CSCs, based therapies in the preclinical setting. while maintaining increased secretion of IFN-gamma, a functional outcome that we have previously coined as 2. INTRODUCTION: NATURAL KILLER split anergy (5-11). In contrast, differentiated tumor cells CELLS KILL AND DIFFERENTIATE CANCER do not down-modulate CD16 expression (7, 8). STEM-LIKE CELLS We have found that CSCs of different origins Natural killer (NK) cells constitute 10% to display low levels of MHC class I, CD54 and programmed 15% of human peripheral blood lymphocytes, and cell death protein ligand 1 (PD-L1), also known as 370 NK cells as therapy to eliminate CSCs in humanized mice Figure 1. Hypothetical representation of osteoclast-expanded super-charged NK cell function in selection and differentiation of CSCs. Recognition of CSCs through CD16 and NKp46 NK cell receptors in a combination with Toll-like or cytokine receptors triggering on NK cells results in selection of CSCs subpopulation and differentiation of selected stem cells by split-anergized NK cells. CD56dimCD16bright NK cells are cytotoxic and are capable of selecting CSCs, whereas CD56dim/brightCD16dim split anergized NK cells lack cytotoxicity and are able to secrete high levels of cytokines (IFN-gamma and TNF-alpha) to support differentiation of selected stem cells. Please note, the receptors shown on NK cells are a partial list of receptors important for the activation of NK cell function. NK, NK cells; NK(SpA) cells, split anergized NK cells; TLR, toll-like receptors; S, stem cells; CD16R, CD16 receptors; NKp46R, NKp46 receptors; IL-2R, IL-2 receptors; DS, dead stem cells. B7H1. A subset of CSCs become targets of cytotoxic translating data obtained from the mouse model to the NK cells, while the remaining CSCs are differentiated human system are structural and functional differences by split anergized/regulatory NK cells through cell- between human and murine immune systems. The cell contact and secretion of membrane bound and major cell population in human blood is represented by secreted forms of TNF-alpha and IFN-gamma (12). neutrophils (50-70%), whereas lymphocytes constitute In addition, differentiation by split anergized NK cells only 30-50%. Murine blood contains mainly lymphocytes leads to inhibition of CSCs growth and upregulation of (75-90%) and B cells are the most abundant type of MHC class I, CD54 and PD-L1 expression, resulting lymphocyte (18). Differences in human and mouse innate in resistance of differentiated tumor cells to NK cell- immune systems include the lack of defensin expression mediated cytotoxicity (12, 13). Overall, our studies by murine granulocytes, expression of different Toll- indicated that NK cells target and differentiate both like receptors on various immune subsets, and healthy and transformed stem-like cells, resulting in phenotypic differences in monocytes, DCs and MDSCs the maturation of target cells and shaping of their (reviewed in (18)). Despite similar proportions of NK microenvironment (Figure 1) (14-17). cells in murine and human blood, their phenotypes and activation dynamics are quite different (18, 19). CD3-/ Data obtained from in vitro cell culture studies CD16+CD56dim phenotype is typical for cytotoxic NK cells, often do not mirror the behavior of primary tumors in whereas the regulatory CD3-/CD16negCD56bright NK cells patients. Mice are chosen as the experimental model mediate differentiation of stem cells in humans (20, 21). in cancer immunology and preclinical testing of cancer Murine NK cells can be characterized by DX5 expression immunotherapeutics as they provide valuable insights and CD11b+/CD27- or CD11b-/CD27+ phenotypes, into the behavior of tumors in the context of full immune respectively (19, 22, 23). We have recently shown that cell repertoire. However, the major limitations of primary non-activated human NK cells mediate low-level 371 © 1996-2017 NK cells as therapy to eliminate CSCs in humanized mice cytotoxicity, but upon short-term IL-2 activation, they solid tumor engraftment compared to nude mice (31). display significant cytotoxicity against a number of Lapidot et al. demonstrated that low engraftment levels human stem-like tumors. In contrast, naïve murine NK of human bone marrow cell suspensions were present, cells do not display any cytotoxicity and require a much but as human cells represented only 0.5%-5% of the longer IL-2 activation period to induce cytotoxicity against total scid recipient marrow population (32), a more target cells (24). Human NK cells utilize KIR proteins as effective model was still needed. The low xenograft inhibitory receptors for MHC class I molecules, whereas reconstitution levels could not only be explained by the murine NK cells use highly divergent structures of Ly49 lack of critical human cytokines but also by the enhanced protein family members. In addition, human NKG2D function of the innate immune system. Despite the block receptors bind to MICA, MICB or ULBP 1-6 ligands, in lymphoid differentiation, C.B17-scid mice develop whereas mouse ligands for NKG2D are different and NK cells, as well as myeloid cells (33). It has been include, HAE60 and Rae1beta (18, 19). Therefore, these shown that, C.B17-scid NK cells could be stimulated differences should be considered and caution should with poly I: C to a higher extent than NK cells from wild be exercised when translating results of mouse tumor type mice, and displayed cytotoxicity against human models to human cancer. mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs) and tumor initiating cells (TICs) In this review, we discuss the utility of humanized (34-36). This enhanced NK cell activity was reported mouse models as a preclinical platform to develop and in strains carrying scid mutations and was considered test novel NK cells based cancer immunotherapies.
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